Atrial fibrillation (AF) increases the risk of stroke, heart failure, dementia and death. The prevalence of AF doubles for each advancing decade of life and multiple data sources suggest that the prevalence of AF is increasing over time. It is estimated that the U.S. prevalence of AF will rise from 2.3 million in 2001 to about 6 to 12 million in 2050. The risk factors for AF are multi-factorial, and include well-known conditions such hypertension and heart failure as well as less familiar traits such as P wave morphology and PR interval. Traditionally, genetic contributions to AF have been considered rare, but in the past five years there have been increasing data demonstrating that all forms of AF, and particularly lone AF, are heritable. Although mutations have been identified in a series of ion channels in families and individuals with AF, these variants are rare causes of the disease. Thus, there remains a significant, but as yet, unexplained genetic basis for AF. The advent of the human genome and HapMap projects and high-throughput genotyping has fundamentally accelerated the ability to discover the genetic contribution to common variation in human disease. Genome-wide association studies (GWAS) have uncovered common single nucleotide polymorphisms (SNPs) underlying risk for diseases such as diabetes and coronary heart disease, and recently AF, as well as quantitative phenotypes such as QT interval. Hence, understanding the role of common genetic variation in AF is of paramount importance and recently achievable. We hypothesize that common variants contribute to variability in AF risk and PR interval in the general population. The specific aims are: Aim 1. To perform a meta-analysis of GWAS to identify common variants predisposing to AF using MGH, Framingham Heart Study (FHS), Rotterdam and Cardiovascular Health Study (CHS). Aim 2. To conduct a meta-analysis of GWAS with PR interval, a quantitative intermediate phenotype for AF, in the FHS, Rotterdam, CHS, MONICA/KORA and Gutenberg Heart (GHS) Studies. Aim 3. To replicate the top 250 AF SNPs and top 100 PR interval SNPs in six additional cohorts. Aim 4. To study mechanisms of SNPs replicated in Aim 3 in cellular and zebrafish model systems. Aim 5. To examine gene-environment (GEI) and gene-gene (epistasis) interactions. In summary, AF is a major source of morbidity and mortality in the population. We bring together a multi- institutional, multi-national team with expertise in AF, genetic epidemiology, statistical genetics, cellular electrophysiology and developmental biology. We propose leveraging existing cohorts and six ongoing GWAS to uncover the genetic contribution to AF and PR interval in the community. The multi-disciplinary breadth of the project will allow translation of the GWAS findings into basic insights of the cellular mechanisms underlying AF. Identification of genes and pathways involved in AF will provide opportunities to advance knowledge of the pathogenesis of AF, and provide novel targets for risk stratification and future therapies. PUBLIC HEALTH RELEVANCE Atrial fibrillation, a common, irregular heart rhythm, increases the risk of stroke and death. Although it is known that atrial fibrillation can be inherited, the specific genetic factors contributing to atrial fibrillation are largely unknown. Investigators from the Framingham Heart Study, Massachusetts General Hospital, Rotterdam, Cardiovascular Health Study and Vanderbilt propose to examine the results of large genetic screening studies, and test the most important findings in other studies in the United States and Europe in order to discover genetic factors contributing to risk of atrial fibrillation.